Receptors Of Plasmacytoid Dendritic Cells And Their Ligands

描述（由申请人提供）：浆细胞样树突状细胞（pDC）代表一种特化免疫细胞群，其响应病毒产生大量I型干扰素（IFN），并作为先天免疫和适应性免疫之间的关键联系发挥作用。我们的长期目标是研究与特定生理环境或条件有关的pDC的功能。中心假设是独特的pDC受体通过与其配体相互作用并激活特定的细胞内途径在pDC的生物学功能中发挥关键作用。我们的假设基于以下观察：1）人pDC受体ILT7激活ITAM介导的信号传导途径以抑制pDC的IFN应答，2）ILT7的潜在配体由一组人乳腺癌细胞系表达，以及3）人pDC受体BDCA 2，一种具有未知配体的C型凝集素，潜在地利用ITAM介导的机制来调节pDC的IFN应答。具体目标是：1）确定ILT7在人pDC中的详细信号传导机制，并研究ITAM介导的途径如何与Toll样受体（TLR）介导的先天免疫应答交叉的基础机制。2)鉴定由人乳腺癌细胞系表达的ILT7的天然配体，并研究其与pDC浸润相关的组织表达。将彻底阐明配体通过与ILT7相互作用对pDC的功能。3)确定BDCA 2使用的详细信令机制。BDCA 2的天然配体将使用能够感测表面BDCA 2接合的报告细胞系统进行筛选。在这一目标中，将测试各种碳水化合物结构、微生物制剂和细胞相关因子。pDC的存在和功能的改变与人类疾病如自身免疫性疾病、感染性疾病和癌症有关。通过对人pDCs独特表达的两种表面受体的研究，通过寻找它们的配体和共同的细胞内信号传导机制，将极大地推进对pDCs生理功能的研究，并可能产生具有治疗潜力的直接分子靶点。

DESCRIPTION (provided by applicant): Plasmacytoid dendritic cells (pDCs) represent a specialized immune cell population that produces large amounts of type I interferons (IFN) in response to viruses and function as a critical linkage between innate and adaptive immunity. Our long-term goal is to study the functions of pDCs pertaining to specific physiological environments or conditions. The central hypothesis is that unique pDC receptors play key roles in the biological functions of pDCs through interactions with their ligands and activating specific intracellular pathways. We based that hypothesis on the observation that 1) human pDC receptor ILT7 activates an ITAM-mediated signaling pathway to inhibit IFN responses by pDCs, 2) the potential ligand of ILT7 is expressed by a group of human breast cancer cell lines, and 3) human pDC receptor BDCA2, a C-type lectin with unknown ligand, potentially utilizes the ITAM-mediated mechanism to regulate pDCs' IFN responses. The specific aims are to: 1) Determine the detailed signaling mechanism of ILT7 in human pDCs and study the underlining mechanism how ITAM-mediated pathway intersects with the Toll-like receptor (TLR)-mediated innate immune responses. 2) Identify the natural ligand of ILT7, which is expressed by human breast cancer cell lines, and study its tissue expression in relation with pDC infiltration. The function of the ligand on pDCs through interaction with ILT7 will be thoroughly elucidated. 3) Determine the detailed signaling mechanism used by BDCA2. The natural ligand for BDCA2 is to be screened using a reporter cell system capable of sensing surface BDCA2 engagement. A wide range of carbohydrate structures, microbial agents and cell-associated factors will be tested in this aim. The altered presence and functions of pDCs have been implicated in human ailments such as autoimmune diseases, infectious diseases and cancer. By focusing on the two surface receptors uniquely expressed by human pDCs through pursuing their ligands and shared intracellular signaling mechanism, the proposed studies will greatly advance research on the physiological functions of pDCs and may generate direct molecular targets with therapeutic potential.